Phenyl-quinolizidines

ABSTRACT

Phenyl-quinolizidines of the general formula ##STR1## wherein X is hydrogen, fluorine, chlorine, lower-alkoxy, lower-alkyl or trifluoromethyl; Y is hydrogen, fluorine, chlorine, lower-alkoxy or lower-alkyl; and R 1  acyl, acylamino or a group A of the formula ##STR2## wherein R 2  is oxygen or sulfur; R 3  is hydrogen or lower-alkyl; and one of R 4  and R 5  is hydrogen and the other is bromine, iodine, cyano, lower-alkoxycarbonyl or sulfamoyl, 
     as racemates or enatiomers, as well as acid addition salts thereof, utilizing various intermediates, are described. The foregoing compounds are useful as neuroleptic, antiemetic and analgesic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 252,540 filed Apr. 9, 1981,now U.S. Pat. No. 4,391,978, which is a continuation-in-part ofapplication Ser. No. 186,936, filed Sept. 12, 1980, now abandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to pharmacologically active phenyl-quinolizidines,their preparation and use, intermediate products in the preparation ofsaid phenyl-quinolizidines and medicaments containing saidphenyl-quinolizidines.

More particularly, the phenyl-quinolizidines of the invention arecharacterized by the formula ##STR3## wherein X is hydrogen, fluorine,chlorine, lower-alkoxy, lower-alkyl or trifluoromethyl; Y is hydrogen,fluorine, chlorine, lower-alkoxy or lower-alkyl; and R¹ is acyl,acylamino or a group A of the formula ##STR4## wherein R² is oxygen orsulfur; R³ is hydrogen or lower-alkyl; and one of R⁴ and R⁵ is hydrogen,and the other is bromine, iodine, cyano, lower-alkoxycarbonyl orsulfamoyl,

in the form of the racemate or the enantiomers, as well as acid additionsalts of such compounds.

In another aspect the invention relates to intermediates of the formulas##STR5## wherein A', Q, R², R⁴, R⁵, R¹³, X, and Y are as hereinafterdescribed.

DETAILED DESCRIPTION OF THE INVENTION

The phenyl-quinolizidines of the invention are characterized by theformula ##STR6## wherein X is hydrogen, fluorine, chlorine,lower-alkoxy, lower-alkyl or trifluoromethyl; Y is hydrogen, fluorine,chlorine, lower-alkoxy or lower-alkyl; and R¹ is acyl, acylamino or agroup A of the formula ##STR7## wherein R² is oxygen or sulfur; R³ ishydrogen or lower-alkyl; and one of R⁴ and R⁵ is hydrogen and the otheris bromine, iodine, cyano, lower-alkoxycarbonyl or sulfamoyl,

as racemate or corresponding enantiomers, as well as acid addition saltsof such compounds.

As indicated in formula I and in various of the formulas which follow,the hydrogen atoms in positions 7 and 9a or 7 and 2 are trans-positionedto one another, so that, in the formulas the 9a- and 2-hydrogen atomsare arbitrarily indicated in the β-position and the 7-hydrogen atom iscorrespondingly indicated in the α-position. The quinolizidines offormula I of the invention, as well as also the correspondingintermediate products and starting materials, are, however, not limitedto this absolute configuaration, but also embrace the correspondingenantiomeric forms, namely compounds with hydrogen in 9aα, 2α and 7β, aswell as the racemates of these two enantiomeric forms.

As used herein, lower-alkyl or lower-alkoxy denotes a group whichcontains 1-6 carbon atoms, especially 1-4 carbon atoms, whereby thegroups with 3 and more carbon atoms can be straight-chain or branched.The acyl residue contained in the acylamino groups R¹ can be derivedfrom organic, saturated, optionally substituted carboxylic acids, forexample from lower alkanecarboxylic acids of 1-6 carbon atoms, such asacetic acid or propionic acid; from lower cycloalkanecarboxylic acidswith 4-7 C-atoms, such as cyclopropanecarboxylic acid,cyclohexanecarboxylic acid; from benzoic acid which can be substituted,for example, by halogen, amino, lower-alkoxy, sulfamoyl and/orlower-alkylsulfonyl, for example, by 4-fluoro, by2-methoxy-4-amino-5-chloro, by 2-methoxy-5-sulfamoyl or by2-methoxy-5-ethylsulfonyl; from aromatic or cycloaliphaticheterocyclocarboxylic acids with at least one oxygen, sulfur or nitrogenatom in the ring, for example, from furan-2-carboxylic acid,thiophene-2-carboxylic acid, 2-oxo-1-pyrrolidine carboxylic acid.Acylamino groups set forth in R¹ can be optionally substituted on thenitrogen, for example, by lower alkyl or phenyl.

Acyl residues set forth in R¹ have an analogous significance as givenabove for the acyl residues contained in acylamino groups set forth inR¹.

As acid addition salts of the phenyl-quinolizidines of formula I of theinvention, there come into consideration pharmacologically orpharmaceutically compatible salts with organic and inorganic acidscustomarily used for salt formation. Examples of such acids are mineralacids, such as, sulfuric acid, nitric acid, phosphoric acid, hydrohalicacids, for example, hydrochloric acid or hydrobromic acids; organicacids, such as tartaric acid, citric acid, aliphatic or aromaticsulfonic acids, maleic acid, mandelic acid and the like. The saltformation can be carried out in a known manner.

Sub-groups within formula I are:

(a) carboxamides of the formula ##STR8## wherein X and Y are aspreviously described and R¹¹ is acylamino, in racemic form and in theform of the corresponding enantiomers, as well as optionally in the formof acid addition salts,

(b) ketones of the formula ##STR9## wherein X and Y are as previouslydescribed, and R¹² is acyl, in racemic form and in the form of thecorresponding enantiomers, as well as optionally in the form of acidaddition salts,

(c) benzimidazolinone (and -thione) derivaties of the formula ##STR10##wherein X, Y and R² -R⁵ are as previously described, in racemic form andin the form of the corresponding enantiomers, as well as optionally inthe form of acid addition salts,

(d) methylbenzimidazole derivatives of the formula ##STR11## wherein X,Y, R⁴ and R⁵ are as previously described in racemic form and in the formof the corresponding enantiomers, as well as optionally in the form ofacid addition salts.

The compounds of formula I possess useful pharmacological properties.Thus, neuroleptic, antiemetic and/or analgesic activities have beenestablished. Especially preferred, due to their pharmacologicalactivities, are compounds of formula I wherein X is hydrogen and Y iso-chloro or o-fluoro. Neuroleptic activity is present in the ketones offormula III, especially, wherein R¹² is p-fluorobenzoyl. Thecarboxamides of formula II, especially wherein R¹¹ iscyclopropanecarboxamido, 2-thiophenecarboxamido,2-oxo-1-pyrrolidinecarboxamido or p-fluorobenzamido, are likewiseneuroleptically active. The benzimidazolinone (and thione) derivativesof formula IV, especially wherein R⁴ is bromine, iodine or cyano and R⁵is hydrogen, as well as also the methylbenzimidazole derivatives offormula IV-2 are likewise neuroleptically active. Carboxamides offormula II wherein R¹¹ is sulfamoylbenzamido orlower-alkylsulfonylbenzamido, especially 5-sulfamoyl-o-anisamido or5-ethylsulfonyl-o-anisamido, are antiemetically active. Carboxamides ofthe formula ##STR12## wherein X and Y is as previously described, R⁶ islower alkyl, preferably ethyl, and R⁷ is lower alkyl or, preferably,phenyl, or phenyl substituted by halogen, lower alkyl or lower alkoxy,

are analgesically active.

Particularly preferred compounds are:

Neuroleptically Active

rac-1-[(9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-5-bromo-2-benzomidazolinone,

rac-1-[(9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-5-iodo-2-benzimidazolinone,

rac-1-[(9aαH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-5-cyano-2-benzimidazolinone,

rac-4-amino-5-chloro-N-[(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-6]-o-anisamide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-5-(ethylsulphonyl)-o-anisamide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-p-fluorobenzamide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]cyclopropanecarboxamide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-2-thiophenecarboxamide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2αyl]-2-oxo-1-pyrrolidinecarboxamide,

rac-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]p-fluorophenylketone.

Antiemetically Active

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-5-sulfamoyl-o-anisamide,

rac-4-amino-5-chloro-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-o-anisamide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-5-(ethylsulfonyl)o-anisamide.

Analgesically Active

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide,

rac-4'-chloro-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide.

rac-3'-chloro-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide,

rac-N-[(9αβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide,

rac-4'-fluoro-N-[(9αβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide,

rac-4'-fluoro-N-[(9αβH)-7β-phenyl-octahydro-2H-quinolizin-2α-yl]-propionanilide,

rac-N-[(9αβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2α-yl]-acetanilide,

rac-N-[(9αβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-N-butylpropionamide,

rac-N-[9αβH)-7β-phenyl-octahydro-2H-quinolizin-2α-yl]-propionanilide.

The phenyl-quinolizidine of formula I are prepared in accordance withthe invention by the following process:

1. To prepare carboxamides of the formula ##STR13## wherein X and Y areas previously described and R¹¹ is acylamino, a primary or secondaryamine of the formula ##STR14## wherein X and Y are as previouslydescribed and Q is a primary or secondary amino group,

is acylated, or in that

2. To prepare ketones of the formula ##STR15## wherein X and Y are aspreviously described and R¹² is acyl, a compound of the formula##STR16## wherein X and Y are as previously described and the ylidenegroup ═CH--R¹³ corresponds to the acyl residue R¹² wherein the oxofunction has been exchanged by hydrogen,

is treated with diborane and hydrogen peroxide and the carbinol obtainedis subjected to an oxidation, or

3. To prepare a compound of the formula ##STR17## wherein X and Y are aspreviously described and A' is A, except that R² is oxygen, and R⁴ andR⁵ are other than bromine and iodine,

a compound of the formula ##STR18## wherein X, Y and A' are aspreviously described, is catalytically hydrogenated, or

4. To prepare a compound of the formula ##STR19## wherein X and Y are aspreviously described and A" is A, except that R² is oxygen and R³ ishydrogen,

a phenylene-diamine of the formula ##STR20## wherein X, Y, R⁴ and R⁵ areas previously described, is condensed with a cyclizing agent of theformula ##STR21## wherein R^(b) and R^(c) are halogen, amino or1-imidazolyl, or with acetic acid or an orthoacetic acid ester, or

5. To prepare compounds of the formula ##STR22## wherein X, Y and R³ -R⁵are as previously described, either (a) a corresponding oxo compound ofthe formula ##STR23## wherein X, Y and R³ -R⁵ are as previouslydescribed, is reacted with P₂ S₅, or (b) a phenylene-diamine of theformula X, described hereinafter, is reacted with thiophosgene,thiocarbonyldiimidazole or CS₂ and subsequently optionally N-alkylated,or

6. Compounds of the general formula ##STR24## wherein X, Y, R², R⁴ andR⁵ are as previously described and R³¹ is lower-alkyl,

a compound of the formula ##STR25## wherein X, Y, R², R⁴ and R⁵ are aspreviously described, is N-alkylated, and in that racemates obtained areoptionally resolved and bases obtained are optionally converted intoacid addition salts.

All of the reactions named in the foregoing process variants 1-6 can becarried out according to known methods.

For the acylation of a primary or secondary amine V, in accordance withprocess variant 1, there come into consideration agents customarily usedfor acylation reactions for example, a reactive derivative of thecorresponding carboxylic acid, for example, the corresponding acidhalide, preferably, the acid chloride, acid anhydride, preferably, amixed anhydride, for example, with chloroformic acid ethyl ester, or thecorresponding acid ester, for example, the methyl or ethyl ester. Thereaction is advantageously effected in the presence of an acid-bindingagent, for example, triethylamine, pyridine or alkali metal carbonate.It can likewise be acylated with the corresponding carboxylic acid inthe presence of a dehydrating agent, such as dicyclohexylcarbodiimide.As the solvent for the acylation there come into consideration the usualinert solvents, for example, benzene, toluene or diethyl ether. Thereaction temperature is not critical and preferably lies in the range offrom about 0° C. to the boiling point of the reaction mixture.

For the preparation of ketones of formula III, an ylidene compound offormula VI is treated first with diborane, thereafter the additionproduct is oxidatively worked-up with hydrogen peroxide to thecorresponding carbinolic epimer mixture and the latter is oxidized tothe ketone. The diborane is preferably generated in situ in a knownmanner, for example, from an alkali metal borohydride and borontrifluoride etherate in an ethereal solvent, such as, ethyleneglycoldimethyl ether, at a temperature in the range of from about -20° C. to+50° C. For the oxidation of the carbinol to the ketone there is used ausual inorganic or organic oxidation agent, for example, chromiumtrioxide, manganese dioxide, alkali metal permanganate, silver carbonateor dimethyl sulfoxideacetic anhydride-triethylamine. The ketone offormula V is obtained as the epimer mixture (2αH+2βH). If desired, thismixture can be transformed into the more stable 2βH-epimer by treatmentwith an alkali metal alcoholate. The oxidation is carried out in aninert solvent, for example, in acetone; the subsequent epimerization ispreferably effected in an alcoholic solvent, for example, in a loweralkanol. The reaction temperature for the oxidation or the epimerizationpreferably lies in the range of from about 0° C. to the boiling point ofthe reaction mixture.

For the preparation of the benzimidazole derivatives of formula IV-3according to process variant 3, the Δ¹ -double bond of the compound offormula VII can be catalytically hydrogenated. As the catalysts, therecan be used usual hydrogenation catalysts, such as PtO₂ or Pd/C forexample.

For the preparation of the benzimidazole derivaties of formula IV-4according to process variant 4, a phenylenediamine of formula VIII canbe condensed with a cyclizing agent of formula IV, for example,phosgene, carbonyldiimidazole or urea, whereby there results abenzimidazolinone derivative of formula IV-1, or also with acetic acidor an orthoacetic acid ester, for example, the trimethyl or triethylester, whereby there is obtained a methylbenzimidazole derivative offormula IV-2.

For the preparation of the thiones of formula IV-5, the oxygen of theimidazole ring of an oxo compound of formula IV-6 can either beexchanged for sulfur with P₂ S₅ in accordance with process variant 5aaccording to known methods, or a phenylenediamine of formula VIII can bereacted with thiophosgene, thiocarbonyldiimidazole or CS₂ in accordancewith process variant 5b in a known manner. The subsequent, facultativeN-alkylation at R³ is effected as indicated for process variant 6.

The process variants 4 and 5b are especially well suited to thepreparation of compounds of formula IV-4 or IV-5 wherein R⁴ is differentfrom R⁵.

For the preparation of compounds of formula IV-7 which are N-alkylatedin the imidazole ring according to process variant 6, a usualN-alkylating agent, for example, a lower-alkyl halide, such as methyliodide, can be used.

A lower-alkoxycarbonyl group R⁴ or R⁵ present in the end product can beoptionally saponified to the carboxy group. For this purpose, the usualacidic, for example, mineral acidic, or basic agents, for example,aqueous alkali hydroxide are suitable. Mineral acid is preferred, forexample, heating with aqueous hydrochloric acid. The temperature is,however, not critical, it can be, for example, in the range of aboutroom temperature to the boiling point of the reaction mixture.

The compounds referred to in the following as intermediate products orstarting materials, insofar as they are not known, can be preparedaccording to known methods. Thus, for example, the primary amines offormula V used as the starting material in process variant I can beobtained in a known manner by oximation of a ketone of the formula##STR26## wherein X and Y are a previously described, with hydroxylaminehydrochloride and reduction of the oxime obtained to the amine byhydrogenation with a noble metal catalyst, such as, Raney-nickel. Thesecondary amines of formula V are obtained, for example, by subjectingthe ketone of formula X to a reductive amination with a primary amine.As the primary amine there come into consideration, preferably, anilineand lower alkylamines, such as, methyl- or ethylamine. As the reducingagent there is used in particular an alkali metal cyanoborohydride, forexample, sodium cyanoborohydride. The preferred 2βH-epimer can beseparated chromatographically from an obtained diastereomer mixture ofan amine of formula V or also by fractional crystallization ofcorresponding addition salts, for example, the hydrochloride.

The ketone X, in turn, can be obtained by decarboxylation ofβ-keto-esters of formula XI with the relative configuration with respectto the positions 1, 7 and 9a indicated in the following formula##STR27## wherein X and Y are as previously described and R^(a) islower-alkyl, see for instance Example 1e.

The β-keto-esters of formula XI can, in turn, be obtained from thecorresponding unsaturated β-keto-esters of formula ##STR28## wherein X,Y and R^(a) are as previously described, in a known manner byhydrogenation, see for instance Example 1f.

The esters of formula XII can be obtained from corresponding5-phenyl-2-piperidones which are optionally substituted in the phenylaccording to known methods, for instance Example 1g.

The ylidene compounds of formula VI referred to as the starting materialin process variant 2 are obtained from the ketones of formula X via aWittig reaction with a compound of the formula R¹³ CH₂ P (phenyl)₃ ⁺ Cl⁻and n-butyl lithium, for example according to the details in Example 7.

The phenylenediamines of formula VIII used in process variant 4 areobtained by reaction of a primary amine V with a correspondinglysubstituted o-halo-nitrobenzene, preferably an o-chloro- oro-fluoro-nitrobenzene derivative and reduction of the nitro group toamino, for example, with hydrochloric acid and iron powder.

The benzimidazolinones of formula IV-8 referred to as the startingmaterial in process variant 6 can be obtained by hydrogenation from thecorresponding unsaturated compounds of formula XIII, with the relativeconfiguration in the positions 7 and 9a indicated in the followingformula, ##STR29## wherein X, Y, R², R⁴ and R⁵ are as previouslydescribed.

By N-alkylation of a compound of formula XIII as in process variant 6there are obtained N-alkylated starting compounds of formula VII, foruse in process variant 3.

The compounds of the formula XIII can, in turn, be obtained from theβ-keto-esters XI by heating with a diamine of the formula ##STR30##wherein R⁴ and R⁵ are as previously described.

The intermediate products or starting materials of formulas V, VI, VIIand VIII also form part of the invention.

The phenyl-quinolizidines of formula I in accordance with the inventiondistinguish themselves by their valuable pharmacological properties. Thecompounds of formula I have neuroleptic, central-depressant,tranqualizing, antiemetic and/or analgesic activity and can accordinglyfind use as antipsychotics or antiemetics or analgesics in the controlof psychoses and neuroses or of nausea or of pain.

The neuroleptic properties of the compounds of formula I can bedemonstrated numerically with the tests described hereinafter:

"Pole Climbing" Test (rat)

For this experimental procedure there was used per dosage a group of 10rats trained to jump on a vertical isolated pole in the experimentalcage, to escape an electroshock (undconditioned stimulus) produced viathe lattice floor immediately after an acoustic signal (conditionedstimulus). The inhibition of the conditioned reaction in the case of 50%of the animals during an observation time of 6 hours is determined bythe parameter ED 50 BCR, the inhibition of the unconditioned reaction isdetermined by the parameter ED 10 BUR.

Spiroperidol-Binding Test (in vitro)

In the in vitro experiments calf striatum was used as the receptor(Lit.: Creese et al., Life Sci. 17, 993 (1975) and incubated with [³H]-spiroperidol analogously to the method described by Fields et al.,Brain Research 136, 578 (1977). With a computer program, there wasdetermined from 4 different concentrations in a triple procedure the IC50 which gives the concentration of the test substance at which a 50%detachment of the specific binding of [³ H]-spiroperidol on the receptortakes place.

Experimental results are compiled in Table A which follows:

                  TABLE A                                                         ______________________________________                                                      Pole Climbing                                                                             Spiroperidol-                                                     BCR   BUR   Binding                                                             ED.sub.50 i.p.                                                                         ED.sub.10 i.p.                                                                         IC.sub.50                                   Compound        (mg/kg)  (mg/kg)  (nanomolar)                                 ______________________________________                                        rac-1-[(9aβH)--7β-(o-                                                               0.08     0.1      3.8                                         Fluorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-5-                                                bromo-2-benzimidazolinone.                                                    HCl                                                                           rac-1-[(9aβH)--7β-(o-                                                               0.1      0.055    8.6                                         Fluorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-5-                                                iodo-2-benzimidazolinone.                                                     HCl                                                                           rac-1-[(9aβH)--7β-(o-                                                               0.65     1.0      50                                          Fluorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-5-                                                cyano-2-benzimidazolinone.                                                    HCl                                                                           rac-4-Amino-5-chloro-N--                                                                      12.5     12.5     30                                          [(9aβH)--7β-(o-chloro-                                              phenyl)-octahydro-2H--                                                        quinolizin-2α-yl]-o-                                                    anisamide                                                                     rac-N--[(9aβH)--7β-(o-                                                              10.0     10.0     135                                         Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-5-                                                (ethylsulfonyl)-0-                                                            anisamide                                                                     rac-N--[(9aβH)--7β-(o-                                                              12.0     5.5      67                                          Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-p-                                                fluorobenzamide                                                               rac-N--[(9aβH)--7β-(o-                                                              6.0      5.5      550                                         Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-                                                  cyclopropanecarboxamide                                                       rac-N--[(9aβH)--7β-(o-                                                              18.0     25.0     123                                         Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-2-                                                thiophenecarboxamide                                                          rac-N--[(9aβH)--7β-(o-                                                              23.0     >30                                                  Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-2-                                                oxo-1-pyrrolidine-                                                            carboxamide                                                                   rac-[(9aβH)--7β-(o-                                                                 3.0      3.0      11                                          Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl] p-                                                fluorophenyl ketone                                                           ______________________________________                                    

The analgesic properties of the compounds were determined numericallyutilizing the tests described hereinafter:

Writhing Test (mouse)

To carry out the experiment, there were employed 8 male mice (20-22 g)per dosage. Sixty (60) minutes after effecting oral administration ofthe test substance, 10 ml/kg of the test solution was injectedintraperitoneally into the test animals. Following a latent period of 5minutes, the number of animals in which over a period of 5 minutes nomore than 1 characteristic writhing symptom (convulsive stretchingmovement of the body) occurred was registered. The ED 50 gives thatdosage at which 50% of the animals show no more than 1 writhing.

Experimental results are compiled in Table B which follows:

                  TABLE B                                                         ______________________________________                                                               Writhing 60'                                           Compound               ED.sub.50 p.o.(mg/kg)                                  ______________________________________                                        rac-N--[(9aβH)--7β-(o-Chlorophenyl)-                                                       0.12                                                   octahydro-2H--quinolizin-2α-yl]-                                        propionanilide                                                                rac-4'-Chloro-N--[(9aβH)--7β-(o-                                                           1.3                                                    chlorophenyl)-octahydro-2H--quinolizin-                                       2α-yl]-propionanilide                                                   rac-3'-Chloro-N--[(9aβH)--7β-(o-                                                           0.95                                                   chlorophenyl)-octahydro-2H--quinolizin-                                       2α-yl]-propionanilide                                                   rac-N--[(9aβH)--7β-(o-Fluorophenyl)-                                                       0.08                                                   octahydro-2H--quinolizin-2α-yl]-                                        propionanilide                                                                rac-4'-Fluoro-N--[(9aβH)--7β-(o-                                                           0.17                                                   Fluorophenyl)-octahydro-2H--quinolizin-                                       2α-yl]-propionanilide                                                   rac-4'-Fluoro-N--[(9aβH)--7β-phenyl-                                                       0.006                                                  octahydro-2H--quinolizin-2α-yl]-                                        propionanilide                                                                ______________________________________                                    

Antiemetic Activity (dog)

A subcutaneous dosage of 0.1 or 0.3 mg of apomorphine hydrochloride/kgbody weight (0.1% or 0.3% solution, solvent 0.9% sodium chloride-water)was administered to pure-bred female Beagle hounds, 12-15 kg, 3 animalsper dosage. For the test, only those animals which showed at least anaverage four-fold vomiting during the hour after apomorphineadministration in 3 separate experiments (in two-week intervals) wereselected. The test compound was administered orally. One (1) hour afteradministration of the test substance, apomorphine hydrochloride wasinjected subcutaneously in the calculated amount of 0.1 or 0.3 mg/kgbody weight. The presence or absence of vomiting was observed during thenext hour. The ED₅₀ is defined as that dosage at which 50% of theanimals are protected against apomorphine-induced vomiting.

Experimental results are compiled in Table C which follows:

                  TABLE C                                                         ______________________________________                                                           Anti-apomorphine                                                              emesis                                                     Compound           ED.sub.50 p.o. (mg/kg)                                     ______________________________________                                        rac-N--[(9aβH)--7β-(o-                                                                 0.8                                                        Chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-5-                                                sulfamoyl-o-anisamide                                                         rac-4-Amino-5-chloro-N--                                                                         2.3                                                        [(9aβH)--7β-(o-                                                     chlorophenyl)-octahydro-                                                      2H--quinolizin-2α-yl]-o-                                                anisamide                                                                     rac-N--[(9aβH)--7β-(o-chloro-                                                          0.38                                                       phenyl)-octahydro-2H--                                                        quinolizin-2α-yl]-5-                                                    (ethylsulfonyl(-o-                                                            anisamide                                                                     ______________________________________                                    

The compounds of formula I of the invention in the form of the racemateor of the enantiomers, as well as in the form of the free bases, as wellas of acid addition salts, find use as medicaments, for example, in theform of pharmaceutical preparations. The pharmaceutical preparations canbe administered orally, for example, in the form of tablets, coatedtablets, dragees, hard and soft gelatin capsules, solution, emulsions orsuspensions. The administration can, however, also be effected rectally,for example, in the form of suppositories, locally or percutaneously,for example, in the form of salves, creams, gels, solutions, orparenterally, for example, in the form of injectable solutions.

To prepare tablets, coated tablets, dragees and hard gelatin capsules,the compounds in accordance with the invention can be admixed withpharmaceutically inert, inorganic or organic excipients. Such excipientsinclude, for example, for tablets, dragees and hard gelatin capsules,lactose, maize starch or derivatives thereof, talc, stearic acid orsalts thereof and the like. For soft gelatin capsules, suitableexcipients are, for example, vegetable oils, waxes, fats, semi-solid,liquid polyols, and the like. Depending on the nature of the activesubstance, no excipients are generally required, however, in the case ofsoft gelatin capsules. To prepare solutions and syrups, suitableexcipients are, for example, water, polyols, saccharose, invert sugar,glucose and the like. To prepare injection, suitable excipients are, forexample, water, alcohols, polyols, glycerine, vegetable oils and thelike. To prepare suppositories, local or percutaneous application forms,suitable excipients are, for examples, natural or hardened oils, waxes,fats, semi-liquid, liquid polyols and the like.

The pharmaceutical preparations can, moreover, also contain preservingagents, solubilizing agents, stabilizing agents, wetting agents,emulsifying agents, sweetening agents, coloring agents, flavoringagents, salts for varying the osmotic pressure, buffers, coating agentsor antioxidants. The pharmaceutical preparations can also contain stillother therapeutically valuable substances.

The foregoing pharmaceutical preparations can contain doses of acompound of formula I in the range of from 0.5 to 100 mg. In the case oforal application, a compound of formula I can be in the range of fromabout 0.05 mg/kg to about 10 mg/kg per day and in the case of parenteralapplication in the range of from about 0.01 mg/kg to 1 mg/kg per day.

The examples which follow further illustrate the invention. Alltemperatures are in degrees centigrade, unless otherwise described.

EXAMPLE I Preparation ofrac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl-5-iodo-2-benzimidazolinone

(a) A solution of 4.80 g ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(2-amino-4-iodo-anilino)-2H-quinolizinein 80 ml of methylene chloride is treated with 3.0 g ofN,N'-carbonyl-diimidazole (93%) and stirred at room temperatureovernight. The precipitated reaction product is filtered off after 20hours, washed with 3×100 ml of methylene chloride and subsequentlydried. There is obtained crystallinerac-1-[(9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl-5-iodo-2-benzimidazolinone.M.p. 271°-274° C. The hydrochloride melts at 265°-267° C.

When in place inrac-(9aβH)-7β-(o-fluorophenyl)-octahydro-2α-(2-amino-4-iodo-anilino)-2H-quinolizinecorrespondingly substituted phenylenediamines are reacted withN,N'-carbonyl-diimidazole, one proceeds to the following products:

    ______________________________________                                        rac-1-[(9aβH)--7β-(R.sub.a)octahydro-2H--quinolizin-2α-yl]    -(B)-2-                                                                       benzimidazolinone:                                                                                 M.p. °C.                                          ______________________________________                                        R.sub.a = o-fluorophenyl                                                                   B =     5-bromo   296-299 (HCl salt)                             o-fluorophenyl                                                                             B =     5-ethoxy- 277-280 (HCl salt)                                                  carbonyl                                                 o-fluorophenyl                                                                             B =     5-cyano   300 (HCl salt)                                 o-fluorophenyl                                                                             B =     5-sulfamoyl                                                                             290-295 (base)                                 ______________________________________                                    

(b) Therac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(2-amino-4-iodoanilino)-2H-quinolizineused as the starting material in Example 1a can be obtained as follows:

5.1 g ofrac-(9αβH)-7β-(o-fluorophenyl)octahydro-2α-(2-nitro-4-iodoanilino)-2H-quinolizineare heated under reflux conditions for 4 hours in 100 ml of methanol,2.0 ml of conc. hydrochloric acid and 1.75 g of iron powder.Subsequently, the reaction mixture is partitioned between 0.5N sodiumhydroxide and chloroform. The chloroform extracts are dried overanhydrous sodium carbonate and then evaporated. From ethanol-n-hexanethere crystallizes therac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(2-amino-4-iodo-anilino)-2H-quinolizine.M.p. 106 -110° C.

rac-(9aβH)-7β-(o-Fluorophenyl)octahydro-2α-(2-amino-4-bromoanilino)-2H-quinolizine,m.p. 153°-155° C., can be manufactured analogously, likewise thecorresponding

    ______________________________________                                        4-carbonitrile       m.p.: 190-193° C.                                 4-sulfonic acid amide                                                                              m.p.: 226-228° C.                                 4-carboxylic acid ethyl ester                                                                      m.p.: 149-156° C.                                 ______________________________________                                    

(c) Therac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(2-nitro-4-iodoanilino)-2H-quinolizineemployed as the starting material in Example 1b can be obtained asfollows:

7.5 g ofrac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)octahydro-2H-quinolizine aredissolved in 75 ml of cyclohexanol (99%), treated with 6.40 g of sodiumcarbonate (anhydrous) and heated to 160° C. At this temperature there isadded dropwise thereto within 3 hours a solution of 9.2 g of2-chloro-5-iodo-nitrobenzene in 75 ml of cyclohexanol (>99%).Subsequently, the reaction solution is held at 160° C. for a further 14hours. After cooling to room temperature, it is filtered off frominorganic residue and the filtrate is evaporated in vacuo. Theevaporation residue is dissolved in 80 ml of hot ethyl acetate and 100ml of methylene chloride, 2 g of active charcoal are added thereto andthe mixture is boiled at reflux for 5 minutes. Thereafter, it isfiltered hot and the filtrate is concentrated to 100 ml. Therecrystallizesrac-(9aβH)-7β(o-fluorophenyl)octahydro-2α-(2-nitro-4-bromo-anilino)-2H-quinolizine. M.p. 175°-177° C. By chromatography of the mother liquoron 150 g of silica gel with n-hexane/diethyl ether 2:1 product is onceagain obtained.

Where in place of 2-chloro-5-iodo-nitrobenzene correspondinglysubstituted o-chloro-nitrobenzenes are employed, then the followingproducts are obtained:

    ______________________________________                                                                M.p. °C.                                       ______________________________________                                        R.sub.a = o-fluorophenyl                                                                    B =    2-nitro-4-bromo-                                                                           175-177                                                          anilino                                                                       2-nitro-4-   135-140                                                          ethoxycarbonyl                                                                2-nitro-4-   235-237                                                          sulfamoyl                                                ______________________________________                                    

(d) Therac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)-octahydro-2H-quinolizineemployed as the starting material in Example 1c can be obtained asfollows:

84.3 g of rac-(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2-oneare heated at relux for 11/2 hours in 1700 ml of methanol with 47.4 g ofhydroxylamine hydrochloride and 94.3 g of potassium carbonate(anhydrous). Subsequently, the methanol is distilled off and the residueis partitioned between 750 ml of water, 600 ml of chloroform and 150 mlof isopropanol. The aqueous phase is back-extracted twice in each casewith 250 ml of a mixture of 200 ml of chloroform and 50 ml ofisopropanol, the combined organic phases are dried over magnesiumsulfate and subsequently evaporated. There result 85.3 g of oxime whichis dissolved in 1.5 l of tetrahydrofuran, 0.5 l of ethanol as well as 1l of (5% g/g ammonia in ethanol) and hydrogenated with 45 g ofRaney-nickel for 30 hours (room temperature, atmospheric pressure).Thereafter, it is filtered off from catalyst and the filtrate isevaporated. From the residue there can be crystallized out bydissolution in 400 ml of ethanol and addition of 130 ml of 5N hydrogenchloride in ethanol 53.5 g of the dihydrochloride salt ofrac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)octahydro-2H-quinolizine. M.p.299°-302° C. The diastereomericrac-(9aβH)-7β-(o-fluorophenyl)-2β-(amino)octahydro-2H-quinolizine isdissolved as the dihydrochloride in the mother liquor.

When in place ofrac-(9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2-onecorrespondingly substituted quinolizidinones are aminated, then thefollowing products are obtained:

rac-(9aβH)-7β-(R_(a))-2α-(amino)octahydro-2H-quinolizine: R_(a)=o-chlorophenyl. M.p. °C. (0.2HCl): 293°-296° C.

(e) The rac-(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2-one usedas the starting material in Example 1d can be obtained as follows:

76.2 g of methylrac-(1αH,9aβH)-7β-(o-fluorophenyl)-octohydro-2-oxo-2H-quinolizine-1-carboxylateare dissolved in 1.2 l of 4N hydrochloric acid and boiled at reflux for7 hours. The cooled reaction solution is subsequently poured on to iceand made alkaline with conc. sodium hydroxide. Extraction with 3×500 lof methylene chloride and evaporation of the organic phase dried oversodium sulfate give 68 g of crude product. From etherhexane there can berecrystallizedrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2-one. M.P.74°-76° C.

When in place of methylrac-(1αH,9aβH-7β-(o-chlorophenyl)octahydro-2-oxo-2H-quinolizine-1-carboxylateequivalent amounts of correspondingly substituted ketoesters aredecarboxylated, the following products are obtained:

    ______________________________________                                        rac-(9aβH)--7β-(R.sub.a)octahydro-2H--quinolizin-2-one:                                      M.p. °C.                                      ______________________________________                                        R.sub.a =                                                                             phenyl                      71-72                                             p-chlorophenyl              80-82                                             p-trifluoromethylphenyl    103-104                                            o-methylphenyl   IR (film) 1726 cm.sup.-1                                     m-methoxyphenyl  IR (film) 1726 cm.sup.-1                                     2,4-dichlorophenyl         116-117                                            2,6-dichlorophenyl         116-118                                            o-chlorophenyl              80-82                                     ______________________________________                                    

(f) The octahydro-carboxylate used in Example 1e as the startingmaterial can, in turn, be obtained from the correspondinghexahydro-carboxylate as follows:

180 g of methylrac-7-(o-fluorophenyl)-3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylateare suspended in 3.6 l of monoglyme (dimethoxyethane), cooled to -30° C.and there are added while stirring 1.33 l of DIBAH (diisobutylaluminiumhydride, 20% solution in toluene). Subsequently, the mixture is stirredat -20° to -30° C. for 1 hour and then hydrolyzed at this temperaturewith 1.72 l of 2N sodium hydroxide. For the working-up, the mixture ispartitioned between 25 l of water and 20 l of chloroform; the organicphase is again washed with 2×5 l of water, dried over magnesium sulfateand evaporated. The crude product is crystallized from etherhexane. Bychromatography of the mother liquor on 1 kg of silica gel with ethylacetate product is once again obtained. There is obtained methylrac-(1αH,9aβH)-7β-(o-fluorophenyl)-octahydro-2oxo-2H-quinolizine-1-carboxylate,m.p. 109°-110° C.

When in place of ethylrac-7-(o-fluorophenyl)-3,5,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylateequimolar amounts of correspondingly substituted educts are reduced withDIBAH, one proceeds to the following compounds:

    ______________________________________                                        Methyl rac-(1αH,9aβH)--7β-(R.sub.a)octahydro-2-oxo-           2H--quinolizine-1-carboxylate:                                                ______________________________________                                        R.sub.a =                                                                            phenyl                     114-116                                            p-chlorophenyl             102-105                                            p-trifluoromethylphenyl    108-111                                            o-methylphenyl              94-98                                             m-methoxyphenyl  IR (film):                                                                              1752, 1723                                                                    1660 cm.sup.-1                                     2,4-dichlorophenyl         116-118                                            2,6-dichlorophenyl         130-131                                            o-chlorophenyl             122-124° C.                          ______________________________________                                    

(g) The hexahydro-carboxylate used in Example 1f as the startingmaterial can, in turn, be obtained as follows:

150 of 5-(o-fluorophenyl)-2-piperidone are dissolved in 2 l of methylenechloride and added dropwise at room temperature while stirring within 60minutes to 410 g of triethyloxonium tetrafluoroborate (Meerwein salt) in1 l of methylene chloride. Subsequently, the mixture is boiled at refluxfor 4 hours and left at room temperature for a further 15 hours. 372 gof potassium carbonate in 370 ml of water are then added dropwise to thesolution which is cooled at 0° C., the mixture being stirredintensively. The mixture is left to stir at room temperature for afurther 2 hours, the methylene chloride phase is subsequently decantedand the residue is extracted with 2×500 ml of methylene chloride. Themethylene chloride phase, dried over potassium carbonate, isconcentrated to an oily, partially crystalline residue, then boiled upin 1 l of hexane and filtered hot. From the filtrate there are obtainedafter evaporation of the hexane, the oily lactim ether:3-(o-fluorophenyl)-6-ethoxy-2,3,4,5-tetrahydropyridine.

The lactim ether is dissolved in 1.4 l of methanol, 1.3 g of anhydrousp-toluenesulfonic acid are added thereto and 85 g of 3-oxo-5-pentenoicacid methyl ester (Nazarov reagent) are added within 60 minutes. After20 hours at room temperature, the readily volatile constituents areremoved in vacuo, the residue is subsequently taken up in methylenechloride and washed with 500 ml of sat. sodium carbonate solution. Themethylene chloride phase, dried over magnesium sulfate, is againconcentrated and the residue is crystallized from ethylacetate-ether=4:1 (800 ml). There is obtained methylrac-7-(o-fluorophenyl)-3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylate.M.p. 165°-167° C.

When in place of 5-(o-fluorophenyl)-2-piperidone equimolar amounts ofcorrespondingly substituted piperidones is used, the following compoundsare obtained:

    ______________________________________                                        Methyl rac-7-(R.sub.a)--3,4,6,7,8,9-hexahydro-2-oxo-                          2H--quinolizine-1-carboxylate:                                                                      M.p. °C.                                         ______________________________________                                        R.sub.a =                                                                              phenyl             148-149                                                    p-chlorophenyl     185-187                                                    p-trifluoromethylphenyl                                                                          144-145                                                    o-methylphenyl     183-184                                                    m-methoxyphenyl    133-134                                                    2,4-dichlorophenyl 153-155                                                    2,6-dichlorophenyl 159-162                                                    o-chlorophenyl     145-147° C.                                ______________________________________                                    

EXAMPLE 2 Preparation ofrac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-2-oxo-5-benzimidazolinecarboxylic acid hydrochloride

70 g ofrac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.yl]-2-oxo-5-benzimidazolinecarboxylic acid ethyl ester hydrochloride are boiled under reflux for 96hours in 500 ml of 5N hydrochloric acid. Subsequently, the mixture iscooled down to 0° C., the reaction product is sucked off over a filter,the residue is washed with 3×100 ml of water and dried in the highvacuum. There resultsrac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-2-oxo-5-benzimidazolinecarboxylic acid hydrochloride. M.p. 285°-295° C.

EXAMPLE 3 Preparation ofrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-5-sulfamoyl-o-anisamide

4.60 g of 2-methoxy-5-sulfamoyl-benzoic acid are dissolved in 150 ml ofmethylene chloride and 50 ml of dimethyl sulfoxide and treated at roomtemperature simultaneously with 2.17 g of chloroformic acid ethyl esterand 2.00 g of triethylamine and stirred for 6 hours. Subsequently, thereis added dropwise a solution of 5.30 g ofrac-(9aβH)-7β-(o-chlorophenyl)-2α-(amino)octahydro-2H-quinolizine in 50ml of methylene chloride, a further 2.30 g of triethylamine are addedand the mixture is left to stir at room temperature for 19 hours. Thereaction solution is poured into 1 lt of water and extracted 2 timeswith 500 ml of methylene chloride each time. The methylene chlorideextracts are washed 2 times with 500 ml of water each time andsubsequently dried over anhydrous sodium carbonate. After evaporation ofthe methylene chloride solution, the residue is dissolved in 600 ml ofmethylene chloride, 400 ml of methanol, 100 ml of ethyl acetate andconcentrated by distillation to a volume of 200 ml of solvent. Therecrystallizesrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-5-sulfamoyl-o-anisamide.M.p. 151°-153° C.

Analogously there are obtained

rac-4-amino-5chloro-N-((9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizinquinolizin-2α-yl)-o-anisamide.M.p. 170°-172° C.

rac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl)-5-(ethylsulfonyl)-o-anisamide.M.p. 145°-155° C.

EXAMPLE 4 Preparation ofrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-o-fluorobenzamide

4.10 g ofrac-(9aβH)-7β-(o-chlorophenyl)-2α-(amino)octahydro-2H-quinolizinedissolved in 40 ml of chloroform are treated at 5° C. with vigorousstirring simultaneously with 3.0 g of 4-fluorobenzoyl chloride in 30 mlof chloroform and 0.8 g of sodium hydroxide in 15 ml of water.Subsequently, the mixture is further stirred for 45 minutes at 5° C. andfor 60 minutes at room temperature. The reaction mixture is subsequentlypartitioned between chloroform and water, the chloroform phase is driedover anhydrous sodium carbonate and evaporated. By recrystallizationfrom ethyl acetate there is obtained crystallinerac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-p-fluorobenzamide.M.P. 200°-202° C.

Analogously there are obtained

rac-N-((9aβH)-7β-(o-chlorophenyl)-ctahydro-2H-quinolizin-2α-yl)cyclopropanecarboxamide.M.p. 193°-195° C.

rac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl)-2-thiophenecarboxamide.M.P. 217°-219° C.

EXAMPLE 5 Preparation ofrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-2-oxo-1-pyrrolidinecarboxamide

5.30 g ofrac-(9aβH)-7β-(o-chlorophenyl)-2α-(amino)octahydro-2H-quinolizine in 100ml of methylene chloride are added dropwise to 3.56 g ofN,N'-carbonyldiimidazole in 100 methylene chloride and subsequentlyfurther stirred at room temperature for 2 hours. Then, the reactionmixture is poured into 1N sodium hydroxide and extracted twice with 300ml of methylene chloride each time. The organic phase, dried overanhydrous sodium carbonate, is subsequently concentrated. As theintermediate product there is obtained cruderac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-imidazole-1-carboxamide.The crude intermediate product is treated in 250 ml of toluene with 12.7g of N-trimethylsilylpyrrolidin-2-one at 80° C. for 17 hours.Subsequently, it is concentrated and the crude reaction mixture ischromatographed over 1 kg of silica gel Merck (0.063-0;2 mm) withchloroform-3% methanol. There is obtainedrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-2-oxo-1-pyrrolidinecarboxamide,m.p. 184°-186° C.

EXAMPLE 6 Preparation ofrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)propionanilide

4.20 g ofrac-N-((9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl)anilinedissolved in 100 ml of abs. toluene are treated with 3.4 ml of propionicacid chloride and 3 ml of triethylamine and heated at 80° C. for 6hours. Subsequently, the reaction solution is partitioned between 2Nsodium hydroxide and chloroform and the aqueous phase is again extractedwith chloroform. The organic phase, dried over anhydrous sodiumcarbonate, is concentrated and chromatographed on a 100 g silica getcolumn with chloroform-1% methanol. There is elutedrac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)propionailidewhich can be recrystallized from ether/n-hexane. M.p. 133°-135° C.

Analogously there is obtained:

rac-4'-chloro-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl)propionanilide,M.p. (HBr salt): 286°-271° C.

rac-3'-Chloro-N-[(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide.M.p. (base) 124°-126° C.

rac-N-[(9aβH)-7β-(o-Fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl)-propionanilide.M.p. (HCl salt) 221°-223° C.

rac-4'-Fluoro-N-[9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilide.M.p. (HCl salt) 240°-242° C.

rac-4'-Fluoro-N-[(9aβH)-7β-phenyl-octahydro-2H-quinolizin-2.alpha.-yl]-propionanilide.M.p. (HCl salt) 238°-240° C.

rac-N-[(9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-acetanilide.M.p. (HCl salt) 232°-236° C.

rac-N-[(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-N-butylpropionamide.M.p. (HCl salt) 175°-177° C.

rac-N-[(9aβH)-7β-phenyl-octahydro-2H-quinolizin-2a-yl]-propionanilide.

The material employed in the above example as the educt can be obtainedas follows:

10.5 g of rac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-oneare dissolved in 150 ml of methanol, treated "green" with 10 g ofmolecular sieve 3 Å and 5 mg of bromocresol. Subsequently, 4.10 g ofaniline are added, 177 g of sodium cyanoborohydride are added theretoand then 2.2N HCl in methanol (a total of 55 ml) is allowed to flow indropwise; as the measurement for the velocity of the dropwise additionthere is used the bromocresol "green" indicator which is standardized atthe transition range green-yellow. After 72 hours reaction time, themixture is partitioned between 2N sodium hydroxide and chloroform, thechloroform extract is dried over anhydrous sodium carbonate andevaporated. The crude product is chromatographed on 250 g of silica get,beginning with 1.5 l of ethyl acetate-n-hexane=1:2; with ethylacetate-n-hexane=1:1 (1 lt) there is eluted therac-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)aniline.

Analogously there is obtained:

rac-4'-chloro-N-((9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl)aniline.

rac-3'-Chloro-N-[(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]aniline.

rac-N-[(9aβH)-7β-(o-Fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]aniline.

rac-4'-Fluoro-N-[(9aβH)-7β-(o-fluorophenyl-octahydro-2H-quinolizin-2α-yl]aniline.

rac-4'-Fluoro-N-[(9aβH)-7β-phenyl-octahydro-2H-quinolizin-2.alpha.-yl]aniline.

rac-N-[(9aβH)-7β-(o-Fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]aniline.

rac-N-[(9aβH)-7β-(o-Chlorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]aniline.

rac-N-[(9aβH)-7β-phenyl-octahydro-2H-quinolizin-2α-yl]aniline.

EXAMPLE 7 Preparation ofrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl)p-fluorophenylketone

14.5 g of p-fluorobenzyl-triphenyl-phosphonium chloride are suspended in100 ml of abs. diethyl ether and treated at 0° C. with 20 ml of n-butyllithium (1.8 molar) and stirred at 0°-5° C. for 1 hour. Subsequently,there is added dropwise thereto a solution of 8.8 g ofrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-one in 150 ml ofabs. diethyl ether and then the mixture is heated at reflux temperaturefor 4 hours. The cooled solution is hydrolyzed with 30 ml of saturatedammonium chloride solution and then partitioned between ethyl acetateand 0.5N sodium hydroxide. The ethyl acetate phase, dried over anhydrousmagnesium sulfate, is evaporated and chromatographed over 100 g ofsilica gel with ethyl acetate-n-hexane=1:1. An oily E/Z mixture ofrac-(9aβH)-7β-(o-chlorophenyl)-2-((p-fluorophenyl)methylene)octahydro-2H-quinolizineis eluted. This mixture is dissolved in 115 ml of ethyleneglycoldimethyl ether (dried netural over aluminum oxide, activity grade I),treated with 1.77 g of sodium borohydride and there is added dropwise atroom temperature a solution of 11.5 g of boron trifluoride etherate in77 ml of ethyleneglycoldimethyl ether. After 1 hours stirring at roomtemperature, the mixture is cooled down to 0°-5° C. and there iscautiously added dropwise a solution of 1.23 g of potassium hydroxide in50 ml of water and subsequently 4.6 ml of hydrogen peroxide (60%) andthen the mixture is heated at reflux temperature. The cooled reactionmixture is partitioned between 2N sodium hydroxide and ethyl acetate,the organic phase is dried over anhydrous magnesium sulfate andevaporated to dryness. This crude product is dissolved in 240 ml ofacetone, cooled to 0°-5° C. and 32 ml of Jones reagent (manufacturedfrom 80 g of chromium trioxide, 64 ml of conc. sulfuric acid, 300 ml ofwater) are added dropwise thereto and the mixture is stirred at 0°-5° C.for 1 hour. Subsequently, the reaction mixture is partitioned between150 ml of sat. sodium acetate solution and 250 ml of ethyl acetate aswell as 200 ml of 2N sodium hydroxide. The organic phase, dried overanhydrous magnesium sulfate, is evaporated to dryness. The crude productis again dissolved in 30 ml of ethyl alcohol and treated with 0.3 g ofsodium ethylate. After 3 hours stirring at room temperature, the mixtureis partitioned between 2N sodium hydroxide and ethyl acetate, theorganic phase is dried over anhydrous magnesium sulfate, treated with 1g of active charcoal and warmed to 50° C., filtered off and evaporatedto dryness. By crystallization from ethyl alcohol-ethyl acetate there isobtainedrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl)p-fluorophenylketone (m.p. 145°-147° C.). From the mother liquor there can be obtainedby chromatography on 100 g of silica gel with ethyl acetate a furtherfraction of product. HCl salt (from methylene chloride-ethyl acetate)m.p.: 256°-258° C.

EXAMPLE 8

    ______________________________________                                        Tablets               Per tablet                                              ______________________________________                                        rac-(9aβH)--7β-(o-Chlorophenyl)-                                                          100      mg                                             octahydro-2H--quinolizin-2α-yl)p-                                       fluorophenyl ketone.HCl                                                       Lactose               202      mg                                             Maize starch          80       mg                                             Hydrolyzed maize starch                                                                             20       mg                                             Calcium stearate      8        mg                                             Total weight          410      mg                                             ______________________________________                                    

The active substance, the lactose, the maize starch and the hydrolyzedmaize starch are mixed and granulated with water to a viscous paste.This paste is passed through a sieve and subsequently dried at 45° C.overnight. The dried granulate is passed through a sieve andsubsequently mixed with the calcium stearate. The mixture obtained ispressed to tablets of a weight of 410 mg and with a diameter of about 10mm.

EXAMPLE 9

    ______________________________________                                        Tablets               Per tablet                                              ______________________________________                                        rac-1-[(9aβH)--7β-(o-Fluorophenyl)-                                                       10.0     mg                                             octahydro-2H--quinolizin-2α-yl]-5-                                      bromo-2-benzimidazolinone.HCl                                                 Lactose               129.0    mg                                             Maize starch          50.0     mg                                             Gelatinized maize starch                                                                            8.0      mg                                             Calcium stearate      3.0      mg                                             Total weight          200.0    mg                                             ______________________________________                                    

The active substance, the lactose, the maize starch and the gelatinizedmaize starch are intimatey mixed with one another. The mixture is passedthrough a comminuting machine and subsequently moistened with water to athick paste. The moist mass is passed through a sieve. The moistgranulate is dried at 45° C. The dried granulate is mixed thoroughlywith the calcium stearate. The granulate is now pressed to tablets of aweight of 200 mg and a diameter of about 8 mm.

EXAMPLE 10

    ______________________________________                                        Tablets                Per tablet                                             ______________________________________                                        rac-1-[(9aβH)--7β-(o-Fluorophenyl)-                                                        10.0     mg                                            octahydro-2H--quinolizin-2α-yl]-5-iodo-                                 2-benzimidazolinone.HCl                                                       Lactose                129.0    mg                                            Maize starch           50.0     mg                                            Gelatinized maize starch                                                                             8.0      mg                                            Calcium stearate       3.0      mg                                            Total weight           200.0    mg                                            ______________________________________                                    

The active substance, the lactose, the maize starch and the gelatinizedmaize starch are intimately mixed with one another. The mixture ispassed through a comminuting machine and subsequently moistened withwater to a thick paste. The moist mass is passed through a sieve. Themoist granulate is dried at 45° C. The dried granulate is thoroughlymixed with the calcium stearate. The granulate is now pressed to tabletsof a content of 200 mg and a diameter of about 8 mm.

EXAMPLE 11

    ______________________________________                                        Tablets               Per tablet                                              ______________________________________                                        rac-N--((9aβH)--7β-(o-chlorophenyl)-                                                      20.0      mg                                            octahydro-2H--quinolizin-2α-yl)-                                        propionanilide.HBr                                                            Lactose               115.0     mg                                            Maize starch          61.0      mg                                            Talc                  3.4       mg                                            Magnesium stearate    0.6       mg                                            Total weight          200.0     mg                                            ______________________________________                                    

The ingredients are inimately mixed with one another and pressed totablets each of 200 mg. Subsequently, they are coated with ethylcellulose and Carbowax.

EXAMPLE 12

    ______________________________________                                        Capsules               Per capsule                                            ______________________________________                                        rac-1-[(9aβH)--7β-(o-Fluorophenyl)-                                                        10.0     mg                                            octahydro-2H--quinolizin-2αyl]-5-                                       bromo-2-benzimidazolinone.HCl                                                 Lactose                175.0    mg                                            Maize starch           30.0     mg                                            Talc                   5.0      mg                                            Total weight           220.0    mg                                            ______________________________________                                    

The active substance, the lactose and the maize starch are intimatelymixed with one another and passed through a comminuting machine. Themixture is now thoroughly mixed with the talc and filled into hardgelatin capsules.

EXAMPLE 13

    ______________________________________                                        Capsules               Per capsule                                            ______________________________________                                        rac-N--((9aβH)--7β-(o-Chlorophenyl)-                                                       10.0     mg                                            octahydro-2H--quinolizin-2α-yl)-                                        propionanilide                                                                Lactose                175.0    mg                                            Maize starch           30.0     mg                                            Talc                   5.0      mg                                            Total weight           220.0    mg                                            ______________________________________                                    

The active substance, the lactose and the maize starch are intimatelymixed with one another and passed through a comminuting machine. Themixture is now mixed thoroughly with the talc and filled into hardgelatin capsules.

EXAMPLE 14

Each 1 ml ampoule contains:

    ______________________________________                                        rac-1-[(9aβH)--7β-(o-Fluorophenyl)-                                                          0.204 mg                                             octahydro-2H--quinolizin-2α-yl]-5-                                                               (2% excess)                                          bromo-2-benzimidazolinone.HCl                                                 Glucose for injection    40.0 mg                                              Water for injection q.s. ad                                                                            1.0 mg                                               ______________________________________                                    

2.04 g of active substance are treated with 400 g of glucose, dissolvedin water for injection and made up to a volume of 10,000 ml with waterfor injection. The solution is either filtered sterile, filled intocolorless ampules, gassed with nitrogen and sealed or filled intocolorless ampules, gassed with nitrogen, sealed and subsequentlysterilized for 30 minutes with flowing steam or autoclaved at 120° C.

EXAMPLE 15 Parenteral Preparation Form (0.5 mg)

Each 1 m. ampoule contains:

    ______________________________________                                        rac-N--((9aβH)--7β-(o-Chlorophenyl)octahydro-                                                  0.510 mg                                           2H--quinolizin -2αyl)propionanilide                                                                (2% excess)                                        Glucose for injection      40.0 mg                                            Water for injection q.s. ad                                                                              1.0 ml                                             ______________________________________                                    

510 g of active substance are treated with 400 g of glucose, dissolvedin water for injection and made up to a volume of 10,000 ml with waterfor injection. The solution is either filtered sterile, filled intocolorless ampules, gassed with nitrogen and sealed or filled intocolorless ampules, gassed with nitrogen, sealed and subsequentlysterilized for 30 minutes with flowing steam or autoclaved at 120° C.

We claim:
 1. A compound of the formula ##STR31## wherein X is hydrogen,fluorine, chlorine, lower-alkoxy, lower-alkyl or trifluoromethyl;Y ishydrogen, fluorine, chlorine, lower-alkoxy or lower-alkyl; and R¹ isacylamino selected from the group consisting of lower-alkanoylamino, (C₄-C₇)-cycloalkylcarbonylamino, 2-furancarbonylamino2-thiophenecarbonylamino or 2-oxo-1-pyrrolidinocarbonylamino whichresidues can be substituted at the nitrogen atom by lower-alkyl orphenyl optionally substituted by halogen, lower-alkyl or lower-alkoxy ora racemate or enantiomer thereof, or a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound, in accordance with claim 1, of theformula ##STR32## wherein X is hydrogen, fluorine, chlorine,lower-alkoxy, lower-alkyl or trifluoromethyl, Y is hydrogen, fluorine,chlorine, lower-alkoxy or lower alkyl and R¹¹ is lower alkanoylamino,(C₄ -C₇)-cycloalkylcarbonylamino, 2-furancarbonylamino,2-thiophenecarbonylamino or 2-oxo-1-pyrrolidinecarbonylamino whichresidues can be substituted at the nitrogen atom by lower-alkyl orphenyl optionally substituted by halogen, lower-alkyl or lower-alkoxy aracemate or, enantiomer thereof, or a pharmaceutically acceptable acidaddition salt thereof.a racemate or, enantiomer thereof, or apharmaceutically acceptable acid addition salt thereof.
 3. A compound,in accordance with claim 2, of the formula ##STR33## wherein X ishydrogen, fluorine, chlorine, lower-alkoxy, lower-alkyl ortrifluoromethyl;Y is hydrogen, fluorine, chlorine, lower-alkoxy orlower-alkyl, R⁶ is lower alkyl and R⁷ is lower alkyl, phenyl, or phenylsubstituted by halogen, lower alkyl or lower alkoxy, ora racemate orenantiomer thereof, or a pharmaceutically acceptable acid addition saltthereof.
 4. A compound, in accordance with claim 2 or 3, wherein X iso-fluoro or o-chloro, Y is hydrogen and R¹¹ is propionanilido,cyclopropanecarboxamido, 2-thiophenecarboxamido or,2-oxo-1-pyrrolidinecarboxamido.
 5. A compound, in accordance with claim2 or 3, wherein X is o-fluoro or o-chloro, Y is hydrogen and R¹¹ is3'-chloro-propionanilido, 4'-chloropropionanilido or4'-fluoropropionanilido.
 6. A compound, in accordance with claim 2 or 3,wherein X and Y are hydrogen and R¹¹ is propionanilido or4'-fluoro-propionanilido.
 7. A compound, in accordance with claim 1,which israc-N-((9aβH)-7β-(o-Chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)cyclopropanecarboxamideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 8. A compound, in accordance with claim 1, which israc-N-((9aβH)-7β-(o-Chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-2-thiophenecarboxamideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 9. A compound, in accordance with claim 1, which israc-N-((9aβH)-7β-(o-Chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)-2-oxo-1-pyrrolidinecarboxamideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 10. A compound, in accordance with claim 1, which israc-N-((9aβH)-7β-(o-Chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)propionanilideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 11. A compound, in accordance with claim 1, which israc-4'-Chloro-N-((9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl)-propionanilideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 12. A compound, in accordance with claim 1, which israc-3'-Chloro-N-[(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilideor enantiomer thereof, or a pharmaceutically acceptable salt thereof.13. A compound, in accordance with claim 1, which israc-N-[(9aβH)-7β-(O-Fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-propionanilideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 14. A compound, in accordance with claim 1, which israc-4'-Fluoro-N-[(9aβH)-7β-(o-fluorophenyl)-octahydro-2H-quinolizin-2α-yl]-propionanilideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 15. A compound, in accordance with claim 1, which israc-4'-Fluoro-N-[(9aβH)-7β-phenyl-octahydro-2H-quinolizin-2.alpha.-yl]-propionanilideor enantiomer thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 16. A compound, in accordance with claim 1, which israc-N-(9aβH)-7β-(o-Fluorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-acetanilideor enantiomer thereof or a pharmaceutically acceptable acid additionsalt thereof.
 17. A compound, in accordance with claim 1, which israc-N-[(9aβH)-7β-(o-Chlorophenyl)-octahydro-2H-quinolizin-2.alpha.-yl]-N-butylpropionamideor enantiomer thereof or a pharmaceutically acceptable acid additionsalt thereof.
 18. A compound, in accordance with claim 1, which israc-N-[(9aβH)-7β-Phenyl-octahydro-2H-quinolizin-2α-yl]-propionanilide orenantiomer thereof or a pharmaceutically acceptable acid addition saltthereof.
 19. A compound in accordance with claim 1 wherein the acylresidue is from furan-2-carboxylic acid, thiophene-2-carboxylic acid, or2-oxo-1-pyrrolidine carboxylic acid.
 20. A quinolizidine-propionanilidecharacterized by the structural formula: ##STR34## wherein R and R₁ arephenyl.
 21. The compound of claim 20 in its isomeric form having a transfused ring juncture.